Despite several recent studies that have emphasized the importance of the kidney in regulating insulin homeostasis, our overall knowledge of renal insulin metabolism is incomplete. In particular, there is a large deficit in our understanding of the factors which determine the uptake of insulin by the luminal and contraluminal aspects of renal tubular cells both in health and disease. In order to further our understanding of physiology of renal insulin metabolism, we will study the determinants of liminal and contraluminal insulin uptake in the isolated perfused kidney and in isolated tubular plasma membranes. These models permit the study of processes that would be difficult or impossible to study in the intact animal. Knowledge gained regarding normal physiology will form the basis of a study of renal insulin metabolism in diabetic ketoacidosis (DKA); a condition associated with abnormal insulin handling by the kidney. In this study we propose to examine firstly, the effects of DKA on insulin metabolism in intact rats and secondly, the individual effects of the major metabolic disturbances associated with DKA on insulin metabolism both in the isolated rat kidney and in isolated tubular plasma membranes. Information derived from this study should provide a better understanding of the pathophysiology of renal insulin metabolism in DKA and thus help place the insulin therapy DKA on a more rational basis.